Atomoxetine (ATM), known as (R)(−)-n-methyl-3-(2-methylphenoxy)-3-phenylpropylamine; has the following structure
and a formula of C17H21NO, a molecular weight of 255.35, and a composition of 79.96 percent C, 8.29 percent H, 5.49 percent N, and 6.27 percent O, by weight. Atomoxetine is the (R)-(−) enantiomer of Tomoxetine. Atomoxetine is a competitive inhibitor of norepinephrine uptake in synaptosomes of rat hypothalamus. Atomoxetine is used for the treatment of Attention-Deficit-Hyperactivity Disorder (ADHD).
Atomoxetine HCl is marketed as STRATTERA®, which is prescribed as oral capsules having dosages of 10 mg, 18 mg, 25 mg, 40 mg, and 60 mg.
The stability of Atomoxetine Hydrochloride is known to be a serious problem. The synthesis of Atomoxetine Hydrochloride involves the use of excess of hydrogen chloride. The presence of free hydrogen chloride in excess can cause degradation in both the last steps of the manufacturing process and in storage. Therefore, for example, Sigma-Aldrich suggests storage at 2° to 8° C. (see: product number T7947, (R)-Tomoxetine HCl, www.signalaldrich.com), to avoid such degradation.
It is well known in the art that, for human administration, safety considerations require the establishment, by national and international regulatory authorities, of very low limits for identified, but toxicologically uncharacterized impurities, before an active pharmaceutical ingredient (API) product is commercialized. Typically, these limits are less than about 0.15 percent by weight of each impurity. Limits for unidentified and/or uncharacterized impurities are obviously lower. Therefore, in the manufacture of APIs, the purity of the products, such as Atomoxetine Hydrochloride, is required before commercialization, as is the purity of the active agent in the manufacture of formulated pharmaceuticals.
It is also known in the art that impurities in an API may arise from degradation of the API itself, which is related to the stability of the pure API during storage, and the manufacturing process, including the chemical synthesis. Process impurities include unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic byproducts, and degradation products.
In addition to stability, which is a factor in the shelf life of the API, the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. For example, the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process. In the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.
As is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product. Therefore, impurities in APIs result primarily from one of two sources, (I) the manufacturing process or synthesis of the API and (II) from the degradation of the API itself.
Once pure Atomoxetine Hydrochloride is obtained, i.e., the Atomoxetine Hydrochloride is substantially free of process impurities, or the process impurities are present in very small, limited amounts at the end of its manufacturing process. Degradation impurities (II), which are related to stability during storage, are the primary source of impurities, as long as contamination is prevented. Manufacturers are required by national and international laws and regulations to submit appropriate documentation to regulatory authorities, proving stability of both the APIs and formulated pharmaceuticals. It is therefore known in the art that stability of the API itself is a necessary condition for commercialization. See, e.g., ICH Q7A guidance for API manufacturers.
Generally, side products, by-products, and adjunct reagents (collectively “impurities”) are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram, or a spot on a TLC plate. (Strobel p. 953, Strobel, H. A.; Heineman, W. R., Chemical Instrumentation: A Systematic Approach, 3rd dd. (Wiley & Sons: New York 1989)). Thereafter, the impurity can be identified, e.g., by its relative position in the chromatogram, where the position in a chromatogram is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the “retention time.”
As is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.
Therefore, an Atomoxetine Hydrochloride having improved stability would be advantageous. The present invention provides such an Atomoxetine Hydrochloride.